Depression: Monocytes on my mind.

Activation of the peripheral immune system contributes to stress-related neuropsychiatric symptoms. Recently in Nature, Cathomas et al. demonstrate that stress-induced social avoidance is mediated by monocyte-derived MMP8 that remodels the extracellular space of the nucleus accumbens.

Microglia contribute to cognitive decline in hypercholesterolemic LDLr-/- mice.

Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr-/- ) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr-/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr-/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr-/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr-/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr-/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr-/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr-/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.

Melanocortin-4 receptors on neurons in the parabrachial nucleus mediate inflammation-induced suppression of food-seeking behavior.

Anorexia is a common symptom during infectious and inflammatory disease. Here we examined the role of melanocortin-4 receptors (MC4Rs) in inflammation-induced anorexia. Mice with transcriptional blockage of the MC4Rs displayed the same reduction of food intake following peripheral injection of lipopolysaccharide as wild type mice but were protected against the anorexic effect of the immune challenge in a test in which fasted animals were to use olfactory cues to find a hidden cookie. By using selective virus-mediated receptor re-expression we demonstrate that the suppression of the food-seeking behavior is subserved by MC4Rs in the brain stem parabrachial nucleus, a central hub for interoceptive information involved in the regulation of food intake. Furthermore, the selective expression of MC4R in the parabrachial nucleus also attenuated the body weight increase that characterizes MC4R KO mice. These data extend on the functions of the MC4Rs and show that MC4Rs in the parabrachial nucleus are critically involved in the anorexic response to peripheral inflammation but also contribute to body weight homeostasis during normal conditions.

ACETAMINOPHEN ATTENUATES PULMONARY VASCULAR RESISTANCE AND PULMONARY ARTERIAL PRESSURE AND INHIBITS CARDIOVASCULAR COLLAPSE IN A PORCINE MODEL OF ENDOTOXEMIA.

ABSTRACT: Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 µg/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-α in blood. As a proof of concept, we injected a high dose of endotoxin (100 µg), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.

Resistance training reduced luteinising hormone levels in postmenopausal women in a substudy of a randomised controlled clinical trial: A clue to how resistance training reduced vasomotor symptoms.

BACKGROUND: Vasomotor symptoms (VMS) are common around menopause. Menopausal hormone therapy is the most effective treatment for VMS. Physical exercise has been proposed as an alternative treatment since physically active women have previously been found to experience fewer VMS than inactive women. In our randomised controlled trial on resistance training to treat VMS, sympoms were reduced by 50% in the intervention group compared with the control group. OBJECTIVES: To propose a mechanism to explain how resistance training reduced VMS and to assess if luteinizing hormone (LH) and follicle stimulating hormone (FSH) were affected in accordance with the proposed mechanism. TRIAL DESIGN AND METHODS: A substudy of a randomized controlled trial on 65 postmenopausal women with VMS and low physical activity who were randomised to 15 weeks of resistance training three times per week (n = 33) or to a control group (n = 32). To be regarded compliant to the intervention we predecided a mean of two training sessions per week. The daily number of VMS were registered before and during the 15 weeks. Blood samples were drawn for analysis of LH and FSH at baseline and after 15 weeks. RESULTS: LH decreased significantly in the compliant intervention group compared with the control group (-4.0±10.6 versus 2.9±9.0, p = 0.028 with Mann-Whitney U test). FSH also decreased in the compliant intervention group compared with the control group, however not enough to reach statistical significance (-3.5±16.3 versus 3.2±18.2, p = 0.063 with Mann-Whitney U test). As previously published the number of hot flushes decreased significantly more in the intervention group than in the control group but there was no association between change in LH or FSH and in number of VMS. CONCLUSIONS: We propose that endogenous opiods such as ß-endorphin or dynorphin produced during resistance training decreased VMS by stimulating KNDγ-neurons to release neurokinin B to the hypothalamic thermoregulatory centre. Through effects on KNDγ-neurons, ß-endorphin could also inhibit GnRH and thereby decrease the production of LH and FSH. The significanty decreased LH in the compliant intervention group compared with the control group was in accordance with the proposed mechanism.

Hippocampal Function Is Impaired by a Short-Term High-Fat Diet in Mice: Increased Blood-Brain Barrier Permeability and Neuroinflammation as Triggering Events.

Worldwide, and especially in Western civilizations, most of the staple diets contain high amounts of fat and refined carbohydrates, leading to an increasing number of obese individuals. In addition to inducing metabolic disorders, energy dense food intake has been suggested to impair brain functions such as cognition and mood control. Here we demonstrate an impaired memory function already 3 days after the start of a high-fat diet (HFD) exposure, and depressive-like behavior, in the tail suspension test, after 5 days. These changes were followed by reduced synaptic density, changes in mitochondrial function and astrocyte activation in the hippocampus. Preceding or coinciding with the behavioral changes, we found an induction of the proinflammatory cytokines TNF-α and IL-6 and an increased permeability of the blood-brain barrier (BBB), in the hippocampus. Finally, in mice treated with a TNF-α inhibitor, the behavioral and BBB alterations caused by HFD-feeding were mitigated suggesting that inflammatory signaling was critical for the changes. In summary, our findings suggest that HFD rapidly triggers hippocampal dysfunction associated with BBB disruption and neuroinflammation, promoting a progressive breakdown of synaptic and metabolic function. In addition to elucidating the link between diet and cognitive function, our results might be relevant for the comprehension of the neurodegenerative process.

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses.

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking αCGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that αCGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.

Fever During Localized Inflammation in Mice Is Elicited by a Humoral Pathway and Depends on Brain Endothelial Interleukin-1 and Interleukin-6 Signaling and Central EP3 Receptors.

We examined the signaling route for fever during localized inflammation in male and female mice, elicited by casein injection into a preformed air pouch. The localized inflammation gave rise to high concentrations of prostaglandins of the E species (PGE2) and cytokines in the air pouch and elevated levels of these inflammatory mediators in plasma. There were also elevated levels of PGE2 in the cerebrospinal fluid, although there was little evidence for PGE2 synthesis in the brain. Global deletion of the PGE2 prostaglandin E receptor 3 (EP3) abolished the febrile response as did deletion of the EP3 receptor in neural cells, whereas its deletion on peripheral nerves had no effect, implying that PGE2 action on this receptor in the CNS elicited the fever. Global deletion of the interleukin-1 receptor type 1 (IL-1R1) also abolished the febrile response, whereas its deletion on neural cells or peripheral nerves had no effect. However, deletion of the IL-1R1 on brain endothelial cells, as well as deletion of the interleukin-6 receptor α on these cells, attenuated the febrile response. In contrast, deletion of the PGE2 synthesizing enzymes cyclooxygenase-2 and microsomal prostaglandin synthase-1 in brain endothelial cells, known to attenuate fever evoked by systemic inflammation, had no effect. We conclude that fever during localized inflammation is not mediated by neural signaling from the inflamed site, as previously suggested, but is dependent on humoral signaling that involves interleukin actions on brain endothelial cells, probably facilitating PGE2 entry into the brain from the circulation and hence representing a mechanism distinct from that at work during systemic inflammation.

Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons.

Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.

NF-κB signaling in tanycytes mediates inflammation-induced anorexia.

OBJECTIVES: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1ß. METHODS: IL-1ß was injected intravenously. To interfere with IL-1ß signaling, we deleted the essential modulator of NF-κB signaling (Nemo) in astrocytes and tanycytes. RESULTS: Systemic IL-1ß increased the activity of the transcription factor NF-κB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-κB signaling, IL-1ß induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E2 (PGE2) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1ß-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. CONCLUSIONS: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus.

IL-6R expressed on CNS vascular endothelial cells contributes to the development of experimental autoimmune encephalomyelitis in mice.

Experimental autoimmune encephalomyelitis (EAE) is the most common model for studying the molecular mechanisms of multiple sclerosis (MS). Here, we examined the CNS-restricted effects of classical interleukin (IL)-6 signaling on the development of EAE, using mice with cell-type specific deletion of the IL-6 receptor (IL-6R). We found that IL-6R deletion in CNS vascular endothelial cells, but not in microglia, ameliorated symptoms of EAE. The milder clinical symptoms in the gene-deleted mice were associated with less demyelination and immune cell infiltration/activation, and lower mRNA levels of the cytokines IL-17 and IL-1ß, as well as the cell adhesion molecules VCAM-1, ICAM-1 and ICAM-2 than what was seen in WT mice. These findings demonstrate that classical IL-6 signaling via endothelial cells of the CNS contributes substantially to the development of MS-like pathology, which should be taken into consideration when conceptualizing future therapeutic approaches.

The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis.

We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a ß3 agonist, UCP-1 and PGC-1α were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the ß3 agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A ß3 antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An α1 /α2b antagonist or a 5HT1A agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.

Immune-mediated febrile response in female rats: Role of central hypothalamic mediators.

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor κB ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 µg/kg) intraperitoneally or CRF (2.5 µg), ET-1 (1 pg), morphine (10 µg) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 µg, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, µ-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.

Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation.

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8-9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

Motivational valence is determined by striatal melanocortin 4 receptors.

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity.

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1-mediated hypothermia and is associated with prostaglandin inhibition in the brain.

The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol's propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol's antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.-Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1-mediated hypothermia and is associated with prostaglandin inhibition in the brain.

Neural Mechanisms of Inflammation-Induced Fever.

Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.

Several behavioral traits relevant for alcoholism are controlled by ɣ2 subunit containing GABAA receptors on dopamine neurons in mice.

The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABAA receptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABAA receptors and activates the mesolimbic dopamine system. Here, we deleted Gabrg2 selectively in dopamine cells of adult mice. The deletion resulted in elevated firing of dopamine neurons and made them less sensitive to drugs acting at GABAA receptors. At the behavioral level, the deletion increased exploratory behavior and augmented both correct and incorrect responding in the go/no-go task, a test often used to assay the response inhibition component of impulsivity. In addition, conditioned place preference to alcohol, but not to cocaine or morphine, was increased. Ethanol-induced locomotor activation was enhanced in the mice lacking Gabrg2 on dopaminergic cells, whereas the sedative effect of alcohol was reduced. Finally, the alcohol drinking, but not the alcohol preference, at a high concentration was increased in the mutant mice. In summary, deletion of Gabrg2 on dopamine cells induced several behavioral traits associated with high risk of developing alcoholism. The findings suggest that mice lacking Gabrg2 on dopaminergic cells could be used as models for individuals at high risk for developing alcoholism and that GABAA receptors on dopamine cells are protective against the development of excessive alcohol drinking.

Interferon-É£ mediated signaling in the brain endothelium is critical for inflammation-induced aversion.

Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-É£ (IFN-É£) in the aversive response to systemic inflammation induced by a low dose (10µg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-É£ expression in the blood and deletion of IFN-É£ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-É£ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-É£ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-É£ action. Collectively, these findings show that circulating IFN-É£ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.